2024-03-28T09:13:23Z
https://u-ryukyu.repo.nii.ac.jp/oai
oai:u-ryukyu.repo.nii.ac.jp:02012159
2023-08-03T05:31:23Z
1642838163960:1642838338003
1642838403551:1642838407312
Cytotoxic Desulfated Saponin from Holothuria atra Predicted to Have High Binding Affinity to the Oncogenic Kinase PAK1: A Combined In Vitro and In Silico Study
Shahinozzaman, Md
Ishii, Takahiro
Takano, Ryo
Halim, Mohammad A.
Hossain, Amzad Md
Tawata, Shinkichi
open access
Holothuria atra
desulfated echinoside B
molecular docking
molecular dynamics
Sea cucumbers have long been utilized in foods and Asiatic folk medicines for their nutritive and health benefits. Herein, three sea cucumber species were investigated and Holothuria atra showed the highest cytotoxicity among these. Next, a desulfated saponin, desulfated echinoside B (DEB), was purified from H. atra through bioassay-guided fractionation. LC-ESI-MS (Liquid chromatography-electrospray ionization mass spectrometry) analysis also showed H. atra to be a rich source of saponins. DEB showed cytotoxicity on cancer cells with IC_50 values of 0.5–2.5 μM, and brine shrimps with an IC_50 value of 9.2 μM. In molecular docking studies, DEB was found to bind strongly with the catalytic domain of PAK1 (p21-activated kinase 1) and it showed binding energy of ―8.2 kcal/mol compared to binding energy of ―7.7 kcal/mol for frondoside A (FRA). Both of them bind to the novel allosteric site close to the ATP-binding cleft. Molecular dynamics (MD) simulation demonstrated that DEB can form a more stable complex with PAK1, remaining inside the allosteric binding pocket and forming the maximum number of hydrogen bonds with the surrounding residues. Moreover, important ligand binding residues were found to be less fluctuating in the DEB-PAK1 complex than in the FRA-PAK1 complex throughout MD simulation. Our experimental and computational studies showed that both DEB and FRA can act as natural allosteric PAK1 inhibitors and DEB appeared to be more promising than FRA.
論文
MDPI
2018-08-31
eng
journal article
VoR
http://hdl.handle.net/20.500.12000/44785
http://hdl.handle.net/20.500.12000/44785
https://u-ryukyu.repo.nii.ac.jp/records/2012159
https://doi.org/10.3390/scipharm86030032
10.3390/scipharm86030032
2218-0532
Scientia Pharmaceutica
86
3
1
13
https://u-ryukyu.repo.nii.ac.jp/record/2012159/files/vol86_n3_p1.pdf